Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Hematology, Komaki City Hospital, Komaki, Japan.
Nat Commun. 2022 Mar 25;13(1):1624. doi: 10.1038/s41467-022-29304-6.
Patient-derived xenografts (PDX) are widely used as human cancer models. Previous studies demonstrated clonal discordance between PDX and primary cells. However, in acute myeloid leukemia (AML)-PDX models, the significance of the clonal dynamics occurring in PDX remains unclear. By evaluating changes in the variant allele frequencies (VAF) of somatic mutations in serial samples of paired primary AML and their PDX bone marrow cells, we identify the skewing engraftment of relapsed or refractory (R/R) AML clones in 57% of PDX models generated from multiclonal AML cells at diagnosis, even if R/R clones are minor at <5% of VAF in patients. The event-free survival rate of patients whose AML cells successfully engraft in PDX models is consistently lower than that of patients with engraftment failure. We herein demonstrate that primary AML cells including potentially chemotherapy-resistant clones dominantly engraft in AML-PDX models and they enrich pre-existing treatment-resistant subclones.
患者来源异种移植物（PDX）被广泛用作人类癌症模型。先前的研究表明 PDX 与原代细胞之间存在克隆分歧。然而，在急性髓系白血病（AML）-PDX 模型中，PDX 中发生的克隆动态的意义尚不清楚。通过评估配对的原发 AML 及其 PDX 骨髓细胞的连续样本中体细胞突变的变异等位基因频率（VAF）的变化，我们在从诊断时多克隆 AML 细胞生成的 57%的 PDX 模型中鉴定出复发或难治性（R/R）AML 克隆的偏倚植入，即使在患者中 VAF<5%时，R/R 克隆也是次要的。AML 细胞在 PDX 模型中成功植入的患者的无事件生存率始终低于植入失败的患者。我们在此证明，包括潜在化疗耐药克隆在内的原发 AML 细胞在 AML-PDX 模型中占主导地位，并且它们富集了预先存在的治疗耐药亚克隆。
